tbuckley/cabot-search huggingface dataset:
TACTIVE-U: Phase 1b/2 umbrella study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER+ advanced or metastatic breast cancer.
Authors: Rachel M. Layman, Katarzyna Joanna Jerzak, John Frederick Hilton, Katherine Clifton, Baha Alkuzweny, Gary Mo, Olga Valota, Julia Perkins Smith, Sibyl Anderson, Cynthia X. Ma
Journal: Journal of Clinical Oncology (2023)

TPS1121 Background: ARV-471, an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in a phase 1/2 study in heavily pretreated patients with ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer. The CDK4/6 inhibitors abemaciclib and ribociclib are approved in combination with endocrine therapy as first- and second-line treatment for ER+/HER2- advanced or metastatic breast cancer; abemaciclib is also approved as monotherapy and in combination with other agents in additional breast cancer settings. ARV-471 combined with abemaciclib or ribociclib showed evidence of synergistic interactions in ER+ breast cancer cells and greater tumor growth inhibition in a xenograft breast cancer model compared with fulvestrant in combination with these agents. Here we describe the first sub-studies of the open-label, phase 1b/2 TACTIVE-U umbrella study, which evaluate the safety and clinical activity of ARV-471 plus abemaciclib (sub-study A; NCT05548127) and ribociclib (sub-study B; NCT05573555) in patients with ER+/HER2- advanced or metastatic breast cancer. Future combination sub-studies will be included in TACTIVE-U. Methods: Patients eligible for sub-studies A and B are aged ≥18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection with ≥1 measurable lesion by RECIST 1.1, and have received ≤2 lines of prior therapy for advanced or metastatic disease and 1 line of any CDK4/6 inhibitor–based regimen in any setting. In sub-studies A and B, patients will receive ARV-471 orally once daily (QD) continuously in a dose escalation/de-escalation approach. In sub-study A, abemaciclib will be given orally twice daily continuously, and in sub-study B, ribociclib will be given orally QD for 21 days followed by 7 days off treatment. For both sub-studies, the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of ARV-471 in combination with abemaciclib or ribociclib. Secondary endpoints of phase 1b are antitumor activity (overall response rate [ORR], clinical benefit rate [CBR], and duration of response [DOR]), progression free survival (PFS), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drugs. Phase 2 further evaluates the antitumor activity of the combinations; the primary endpoint is ORR and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Clinical trial information: NCT05548127 , NCT05573555 .
Decision value of the circulating tumor DNA on the adjuvant anti-Her2 regimens in patients with Her2-positive breast cancer treated with neoadjuvant therapy.
Authors: Po-Han Lin, Li-Wei Tsai, Chiao Lo, Sung-Hsin Kuo, Chiun-Sheng Huang
Journal: Journal of Clinical Oncology (2023)

558 Background: A significant proportion of patients with early-stage Her2-positive breast cancer are treated with neoadjuvant therapy (NAT). Previous studies suggested the presence of circulating tumor DNA (ctDNA(+)) after NAT was a significant predictor for recurrence in early-stage Her2-positive breast cancer. However, it is unknown whether the ctDNA(+) was able to guide adjuvant anti-Her2 regimen for patients with early-stage Her2-positive breast cancer? Methods: We enrolled 117 patients who had Her2-positive breast cancer and received NAT. CtDNA was collected before and after NAT as well as detected by Oncomine breast cell-free DNA assay. Adjuvant anti-Her2 regimens were classified as T-DM1 and non-T-DM1. Recurrence-free survival (RFS) was estimated by Kaplan-Meier method and hazard ratio (HR) with 95% confidence interval (CI) was analyzed by Cox proportional hazards regression model. Results: Of the 117 patients enrolled, there were 18 patients receiving adjuvant T-DM1 and 99 receiving trastuzumab (N = 70) or trastuzumab plus pertuzumab (N = 29). CtDNA(+) was observed in 79 patients before NAT while 32 patients remained ctDNA(+) after NAT. Multivariate Cox regression model showed that ctDNA(+) after NAT (HR 3.497 95% CI 1.364-8.964, p = 0.009) was an independently poor factor that predicted recurrence, after adjustment with clinical and pathologic parameters. Non-pCR was associated with an inferior trend of survival but not a statistically significant factor of recurrence. Patients who received adjuvant T-DM1 had a reduced risk of recurrence (HR 0.118, 95% CI 0.015-0.931, p = 0.043) in the multivariate analysis. Further analysis of the prognostic value of adjuvant T-DM1 therapy in context with and without ctDNA, we divided patients into 4 subgroups: ctDNA(-)/non-T-DM1, ctDNA(-)/T-DM1, ctDNA(+)/non-T-DM1 and ctDNA(+)/T-DM1. Our data revealed that patients with ctDNA(+)/T-DM1 had a significantly better RFS than those with ctDNA(+)/non-T-DM1 (p = 0.019). The 5-year RFS was similar between patients with ctDNA (+)/T-DM1 and those with ctDNA(-) after NAT. Conclusions: The presence of ctDNA in patients with early-stage Her2-positive breast cancer after NAT was independently associated with disease recurrence; however, ctDNA(+) after NAT became inconsiderable when patients were treated with adjuvant T-DM1 therapy, which represented ctDNA(+) as an important factor determining adjuvant anti-Her2 regimen.
Complicating breast cancer treatment: Reasons patients present to the ED.
Authors: Jayla Hsiung, Kamil Taneja, Karan Patel, William Benedict, Kenyon Sprankle, Michael J. Diaz, Jules A. Cohen
Journal: Journal of Clinical Oncology (2023)

e13668 Background: Breast cancer is a very common cancer that provides a significant amount of stress on patients’ lives. These patients can have many cancer-related complications, which lead them to present to the ED. However, few studies have identified common reasons for these patients to present to the ED and factors associated with high risk of admission. Methods: We utilized the 2006-2012 Nationwide Emergency Department Sample to identify the common primary diagnoses of breast cancer patients in the ED. A multivariate logistic regression was used to identify characteristics that were significantly associated with a higher chance of inpatient admission. A p-value less than 0.05 was considered significant. Results: Between 2006 and 2012, 2,160,701 breast cancer patients presented to the ED. Most patients were at least 80 years old (53.0%), female (99.1%), Medicare beneficiaries (64.4%), of the highest income quartile (26.2%), living in the South (36.8%), presented to non-trauma hospitals (52.7%), and presented to metropolitan non-teaching hospitals (44.8%). Most patients were admitted (53.1%). The most common primary diagnoses of breast cancer patients were chest pain (5.4%), urinary tract infection (3.3%), pneumonia (3.1%), secondary malignancy (3.0%), and cardiac arrhythmia (3.0%). The primary diagnoses associated with the highest risk of inpatient admission are the following: septicemia (odds ratio: 39.4, 95% confidence interval (CI): 33.8-45.9,p &lt; 0.001), femur fracture (OR:19.1, 95% CI: 16.6-22.0,p &lt; 0.001), secondary malignancy (OR:17.7, 95% CI: 16.2-19.4,p &lt; 0.001), acute cerebrovascular disease (OR:5.8, 95% CI:5.3-6.3,p &lt; 0.001), pneumonia (OR:4.9, 95% CI:4.7-5.2,p &lt; 0.001), and complication of previous surgical or medical therapy (OR:2.2, 95% CI:2.0-2.3,p &lt; 0.001). Primary diagnoses associated with a lower risk of admission are the following: contusion (OR:0.06, 95% CI:0.06-0.07,p &lt; 0.001), abdominal pain (OR:0.14, 95% CI:0.13-0.15,p &lt; 0.001), and connective tissue disorder (OR:0.17, 95% CI:0.16-0.19,p &lt; 0.001). Interestingly, patients that paid with Medicaid (OR:0.84, 95% CI:0.79-0.89,p &lt; 0.001) or private insurance (OR:0.89, 95% CI:0.86-0.93,p &lt; 0.001) were less likely to be admitted. Furthermore, uninsured patients were also less likely to be admitted (OR:0.52, 95% CI:0.48-0.57, p &lt; 0.001). Conclusions: Breast cancer patients frequently present to the ED for many reasons, with septicemia and femur being the most severe diagnoses. Physicians should keep these risk factors in mind to prevent these complications and reduce patient stress.
Mutation profiling of gliomas based on sex, age, and family history.
Authors: Xue Fan, Ming Yang, Xiaoni Zhang, Hui Li, Xuebin Wan, Yuanyuan Liu, Shuxiong Zhou
Journal: Journal of Clinical Oncology (2023)

e14041 Background: The gender, age and family history of patients are important factors leading to the mutation of tumor-related genes. Currently, the relationship between these factors and tumor gene mutations in glioma is unclear. Therefore, we identified the effect of gender, age, and family history on cancer-susceptibility gene mutations in patients with glioma through retrospective analysis. Methods: A total of 735 FFPE tissue samples were collected from 2019 to 2022 in glioma patients, and sequenced by HapOnco StarPanel NGS Assay (covering 1326 genes + 3 viral sequences). Results: (1) These mutations were categorized into four subgroups according to the age of the patients. In the 0-20 years group, the main mutated genes were TP53 (63.64%), BRAF (36.36%), and H3F3A (22.73%) in females (n = 22) and TP53 (26.92%), BRAF (46.15%) and H3F3A (19.23%) in males (n = 26), respectively. In the 21-40 age group, the gene mutation rates of TP53, IDH1, and TERT were 71.43%, 58.57%, and 21.43% in female (n = 70), whereas these genes ( TP53, 72.90%; IDH1, 63.55%; TERT, 35.51%) displayed higher mutation frequency in males (n = 107). In the 41-60 age group, TERT (61.70%), TP53 (43.97%), and IDH1 (36.88%) in females (n = 141) showed obvious difference compared with that ( TERT, 54.33%; TP53, 47.12%; IDH1, 42.31%) in male (n = 208). Aged patients, especially those over 61 years, the most mutated genes were TERT (63.08%), EGFR (60.00%), and TP53 (49.23%) in female (n = 65), respectively. However, the most commonly mutated genes in male presented apparently different than the genes in female such as LRP1B, CSMD3, SYNE1, NF1, ATM, PTEN, RB1, TERT, MET, and TP53. (2) Generally, the peak incidence of patients with glioma is between 41-60 years old. We found the percentage of the total incidence of glioma patients was associated with the family history (positive, 56.25%; negative, 47.68%). Conclusions: The gene mutated rates were depending on the age, sex, and family history in glioma, which might reveal potential effect for biomarker detection in combination with these categories in clinical.
CCT6A and triple-negative breast cancer metastasis: Activating the AKT/MDM2/P53 pathway.
Authors: Mengdi Yang, Jianing Cao, Duancheng Guo, Zhonghua Tao, Xichun Hu
Journal: Journal of Clinical Oncology (2023)

e13087 Background: Triple-negative breast cancer (TNBC) patients are prone to distant recurrence and poorer prognosis. The key molecules and underlying mechanisms of TNBC's aggressive phenotype remain to be further clarified. Methods: First, using the Kaplan-Meier Plotter ( https://kmplot.com/analysis ) and analyzing our collected clinical samples, we established the expression pattern and clinical value of the chaperonin containing TCP1 subunit 6A (CCT6A) in TNBC. We carried out the Cell Counting Kit-8 (CCK8), Transwell, and flow cytometry assay in the TNBC cell lines including MDA-MB-231 and BT549 to assess the effects of knockdown and overexpress of CCT6A. The mechanism of CCT6A in TNBC was identified by using the RNA-seq, KEGG analysis and Co-Immunoprecipitation Mass Spectrometry. Rescue assays verified the role of the AKT Serine/Threonine Kinase 1 (AKT) / Mouse double minute 2 homolog (MDM2)/P53 pathway on CCT6A. Then, the effect of CCT6A on tumor progression and metastasis in vivo was evaluated by the mouse models of tumorigenesis in situ and caudal artery lung metastasis. APG115, a pharmacological p53 activator and immune stimulatory MDM2 inhibitor, combined with anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody Ipilimumab was found to prevent TNBC metastasis. Finally, we did a profiling of the tumor immune environment in mice. Results: CCT6A was highly expressed in TNBC ( p&lt;0.0001), and patients with high expression of CCT6A had poor prognosis ( p=0.0053, HR=2.36 [1.27-4.39]). Of note, CCT6A was significantly associated with lymph node metastasis ( p&lt;0.0001). CCT6A promoted cell proliferation, migration, and invasion while inhibiting cell apoptosis and achieving G1/S stage arrest through gain- and loss-of-function approaches. In terms of mechanism, Co-IP and Immunofluorescence assay verified that CCT6A interacted with Keratin 10 (KRT10) which can promote tumor metastasis. Compared with the control group, RNA-seq, and KEGG analysis suggested that AKT/MDM2/P53 signaling was inhibited after knockdown of CCT6A in MDA-MB-231. Furthermore, we found that the tumor volume and the number of lung metastasis sites were significantly reduced in the APG115 combined with Ipilimumab treatment group. Flow cytometry and multiple Immunofluorescence assay showed that TGF-β level from regulatory T cells decreased, while IFN-γ amount from CD8+T cells significantly increased with the combination (both p&lt;0.05). Conclusions: Our research demonstrated that CCT6A can enhance metastasis of triple-negative breast cancer via up-regulating the AKT/MDM2/P53 pathway. These results provide rationales for MDM2 inhibitor combined with anti-CTLA-4 antibody for preventing TNBC metastasis.
Prognosis of patients with HER2-low breast cancer brain metastasis: A single-institution experience.
Authors: Hangcheng Xu, Yan Wang, Yiqun Han, Yun Wu, Qiang Sa, Jiayu Wang
Journal: Journal of Clinical Oncology (2023)

e13109 Background: Many patients with breast cancer were reported to suffer from brain metastasis in the advanced setting. Traditionally, the HER2-low entity was classified as HER2-negative when evaluating prognosis and administrating treatment in patients with breast cancer brain metastasis (BCBM). Trastuzumab deruxtecan (T-DXd) was proved to have potent efficacy in HER2-low breast cancer, even with brain metastasis, which made this subtype a distinct entity. However, the evidence regarding HER2-low BCBM is scarce. Methods: Based on the clinical database of our institution, the BCBM patients with available HER2 status between January 2010 and July 2021 were selected. The enrolled patients with HER2 1/2+ in immunohistochemistry and negative for fluorescence in situ hybridization (FISH) were classified as HER2-low. The comparisons were conducted between HER2-low and HER2-zero category. We predefined the primary endpoint as the overall survival (OS) after the diagnosis of BCBM, which were further analyzed basing the status of hormone receptor (HR). The Kaplan–Meier curves with log-rank test and Cox proportional hazards model were utilized to analyze the survival outcomes. Results: A total of 272 cases were included in the database, among which the patients with HER2-zero (n=64) and HER2-low (n=71) subtypes were analyzed eventually. The OS of patients with HER2-low BCBM was better than the HER2-zero counterparts in the overall population (p=0.002) and the HR-negative group (p=0.008), while the similar tendency was not observed in the HR-positive patients. Moreover, the Cox regression analysis demonstrated that the HER2-low status was a significant prognostic factor for the better clinical outcome in the HR-negative patients (p=0.046 for multivariate analysis). Conclusions: The patients with HER2-low BCBM had better prognosis than the HER2-zero counterparts, especially in the HR-positive subgroup. The low expression of HER2 is supposed to be related to the long-term survival of BCBM patients.
Ozone-loaded Pt(IV) prodrug self-assembled micelles with high bioavailability, low toxicity as a novel irradiation-controlled release treatment and the immune microenvironment editor for triple-negative breast cancer.
Authors: Dan Zheng, Ting Luo, Hubing Shi, Tianyue Xu
Journal: Journal of Clinical Oncology (2023)

e12575 Background: A considerable part of TNBC shows poor response to the immune checkpoint blockades (ICBs) due to the immunosuppressive microenvironment. Chemotherapy performs well in synergizing with ICBs by improving tumor immunogenicity or eliminating the immunosuppressive tumor microenvironment. However, limited bioavailability, significant systematic toxicity and immunosuppressive metastatic niche induced by chemotherapy restrict its systematic application. Methods: We constructed the Pt(IV)-prodrug self-assembled micelles of O 3 _PFD@PtF with an ozone-loaded perfluorodecalin as the core (O 3 _PFD), and Pt(IV)-fluorocarbon chains assembled micelle as the shell (PtF). Results: The particle sizes of the prodrug were about 130.5 nm of PFD@PtF and 174.7 nm of O 3 _PFD@PtF, and both of the two showed good stability in the environment of different pH value and temperature. The Pt(IV) in the prodrug can be reduced and released in the sodium citrate solution. In addition, ozone was well stabilized by the PFD@PtF as the ROS donor and decomposed rapidly upon the irradiation excitation. O 3 _PFD@PtF boosted the level of GSH by promoting the intracellular redox balance with ROS and then the Pt(IV) was reduced to Pt(II) to release only within tumor. The prodrug was efficiently endocytosed into TNBC cells. Compared to cisplatin, a higher amount of Pt(II) was detected inserted into DNA in the O 3 _PFD@PtF combining irradiation treating group, which was released through depleting GSH donated by ROS. Accordingly, a remarkable reduction in IC50 was recorded in TNBC cells when O 3 _PFD@PtF was applied synergizing with irradiation. Furthermore, a relatively low IC50 was detected in non-ozone loaded prodrug-treated TNBC cells, which was attributed to the high concentration of background GSH, whereas the IC50 of PtF in Hacat was significantly higher than in other treating groups due to the low concentration of background GSH. Excellent inhibiting rates of the TNBC cells proliferation were observed in O 3 _PFD@PtF plus irradiation group 96 hours after treating, outperforming the conventional cisplatin plus irradiation group. We also observed a medium proliferation rate of TNBC cells in O 3 _PFD@PtF treating group in the absence of irradiation, which may be attributed to the Pt(II) released by the automatic decomposition of ozone. More importantly, cisplatin was reported to induced immunogenic cell death when synergizing with irradiation, but not alone. The dual potential to enhance TNBC proliferation inhibition and edit its immune microenvironment are now continuously detected. Conclusions: As a novel nano-prodrug with high efficiency and safty, O 3 _PFD@PtF plus irradiation is expected to improve the response of TNBC to ICBs by editing the tumor immune microenvironment.
The ARETHA study: A phase 2 randomized control trial of eribulin with evexomostat (SDX-7320) or placebo for patients with metastatic triple-negative breast cancer (TNBC) and metabolic dysfunction.
Authors: Sherry Shen, Verna Solomon, Dominiq Williams, Mark E. Robson, Larry Norton, Tiffany A. Traina, Neil M. Iyengar
Journal: Journal of Clinical Oncology (2023)

TPS1131 Background: The prognosis for advanced/metastatic TNBC remains poor and novel therapeutic strategies are urgently needed. Insulin resistance and obesity contribute to TNBC progression and are independent predictors of worse survival. Methionine aminopeptidase 2 (MetAP2/p67) is overexpressed in many tumor types including breast. MetAP2 inhibitors exhibit broad anti-tumor activity and attenuate the effects of metabolic dysfunction on tumor growth. Evexomostat (SDX-7320) is a second-generation MetAP2 inhibitor that improved insulin sensitivity, reduced fat mass, and normalized adipokine levels in preclinical models of obesity and reduced tumor growth in TNBC preclinical models. In phase 1 trials, evexomostat monotherapy partially restored insulin sensitivity, reduced adipokines, and showed anti-metastatic effects in patients with advanced solid tumors. The goal of this phase 2 study is to test whether evexomostat prevents worsening of insulin resistance and augments tumor response in patients with metastatic TNBC and metabolic dysfunction in combination with eribulin chemotherapy, a standard of care treatment option after prior anthracycline and taxane exposure. Methods: This is a single-center phase 2 randomized control trial of evexomostat, a MetAP2 inhibitor, and eribulin chemotherapy. Key eligibility criteria include metastatic TNBC, measurable disease or ≥1 predominantly lytic bone lesion, baseline hemoglobin A1c &gt;5.5% and/or BMI ≥30 kg/m2, and ≤2 prior lines of therapy in the advanced/metastatic setting. Patients with uncontrolled or insulin-dependent type II diabetes, or who require combination antihyperglycemic therapy are excluded. During the safety run-in period, 15 patients will be assigned to receive evexomostat 49 mg/m2 Q2 weeks and eribulin 1.4 mg/m2 on days 1 &amp; 8 of a 21-day cycle. Upon safety confirmation, an additional 40 patients will be randomized 2:1 to receive evexomostat or placebo with eribulin. The primary endpoint is metabolic efficacy assessed by change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score. Secondary endpoints include objective response rate, progression-free survival, safety and tolerability, patient-reported outcomes, and changes in metabolic markers and body composition. Historically, HOMA-IR scores double during chemotherapy, and this trial will test whether evexomostat attenuates the expected HOMA-IR rise. This trial will have &gt;90% power to detect a difference between a 1.5-fold change in HOMA-IR in the control arm vs. no change in the evexomostat arm while controlling the Type I error at 5%. As of Feb 2022, 3 patients are enrolled; total accrual of 61 patients is planned with a goal of 55 evaluable patients. Clinical trial information: NCT05570253 .